黄芪多糖对颅脑损伤大鼠学习记忆能力及海马BDNF表达的影响

目的探讨黄芪多糖(APS)对颅脑损伤大鼠学习记忆能力及海马组织脑源性神经生长因子(BDNF)表达的影响。方法将30只成年雄性SD大鼠按随机数字表随机分为3组:假手术组、TBI组、APS组,每组10只。TBI组和APS组建立颅脑损伤大鼠模型,假手术组不建模型。假手术组、TBI组分别给予生理盐水灌胃,APS组给予APS悬液(100 mg/kg)灌胃;每天1次,持续8周。采用Morris水迷宫实验测试大鼠学习记忆能力。水迷宫实验结束后,RT-PCR与Western blot测定海马组织BDNF mRNA和蛋白表达水平。结果与假手术组比较,TBI组大鼠逃避潜伏期明显延长(P0.05),平台象限路径百分比和平台象限时间明显缩短(P0.05),海马组织BDNF mRNA和蛋白表达水平明显降低(P0.05);与TBI组比较,APS组大鼠逃避潜伏期明显缩短(P0.05)、平台象限路径百分比和平台象限时间明显延长(P0.05),海马组织BDNF mRNA和蛋白表达水平明显升高(P0.05)。结论APS能够减轻颅脑损伤所致的大鼠学习记忆能力减退,可能与提高BDNF表达水平有关。     

褪黑素对Alzheimer病模型大鼠认知功能和海马tau蛋白过度磷酸化的影响

目的 研究褪黑素(MT)对Alzheimer病(AD)模型大鼠认知功能和海马tau蛋白过度磷酸化的影响.方法 给大鼠海马内注射凝聚态β-淀粉样蛋白(Aβ)25-35制作AD模型;MT组大鼠从制模前7 d至制模后19 d每日腹腔注射MT,AD组大鼠制模后腹腔注射生理盐水;用Morris水迷宫试验检测大鼠的认知功能,银染法观察海马神经元形态,免疫组化法观察过度磷酸化tau蛋白的表达,并与正常对照组比较.结果 MT组大鼠Morris水迷宫试验结果明显好于AD组(均P＜0.001);海马CA1区磷酸化tau蛋白阳性细胞数(60.0±2.3)明显少于AD组(98.4±3.0)(P＜0.001),与正常对照组比较差异无统计学意义;海马CA1区神经元纤维形态较AD组规则.结论 MT可明显改善AD大鼠的认知功能,并且抑制海马tau蛋白的过度磷酸化.     

轻型颅脑损伤对大鼠脑源性神经营养因子基因表达的影响及意义

目的探讨轻型颅脑损伤对大鼠脑源性神经营养因子(BDNF)基因表达的影响及意义.方法120只成年SD大鼠根据性别不同分为雌性对照组、雌性实验组、雄性对照组和雄性实验组,每组30只.两实验组建立侧位液压冲击轻型颅脑损伤模型.Morris水迷宫试验测试大鼠学习记忆能力,RT-PCR检测海马中BDNF mRNA的表达.结果水迷宫定位航行试验第4天,同性别大鼠实验组平均逃逸潜伏期较对照组明显延长(P＜0.05);空间探索试验同性别大鼠实验组寻找平台潜伏期较对照组明显延长(P＜0.05),穿越平台次数较对照组减少(P＜0.05);同性别大鼠实验组大脑海马中BDNFmRNA的表达显著低于对照组(P＜0.01).结论侧位液压冲击轻型颅脑损伤会降低模型鼠大脑海马中BDNF mRNA的表达,并可能因此导致大鼠学习记忆能力下降.     

丙戊酸钠对慢性酒中毒模型大鼠学习记忆损害的影响

目的探讨慢性酒中毒对大鼠学习记忆的影响及丙戊酸钠(VPA)的干预效应及其可能机制。方法将56只SD大鼠随机分为酒中毒模型组、VPA干预组、VPA对照组和正常对照组。以乙醇浓度梯度递增式的方式灌胃8周制作慢性酒中毒模型,而第5周始酒中毒模型组腹腔注射生理盐水,VPA干预组于第5～8周腹腔注射VPA,VPA对照组灌注等体积的生理盐水4周后第5～8周给予VPA。8周后每组随机选取7只采用Morris水迷宫和Y迷宫检测大鼠的学习记忆功能,其余7只用Westernblot检测海马脑源性神经营养因子(BDNF)蛋白的表达含量。结果与正常对照组相比,酒中毒模型组大鼠水迷宫的逃避潜伏期显著延长(P0.05),空间探索次数显著减少(P0.05);Y迷宫中2d的错误次数显著增加(P0.01);海马BDNF含量下降(P0.05)。与酒中毒模型组相比,VPA干预组大鼠的行为学成绩均得到改善(P0.01),海马BDNF含量显著增加(P0.01),与正常对照组的差异无统计学意义(P0.05)。VPA对照组与正常对照组各项指标的差异均无统计学意义(P0.05)。结论慢性酒中毒可以导致大鼠学习记忆障碍,而VPA对酒精诱导的学习记忆损害有干预作用,海马BDNF表达增加可能是其作用机制之一。     

胰高血糖素样肽1(GLP-1)改善阿尔茨海默病大鼠模型的认知功能及其机制研究

目的 探讨胰高血糖素样肽1(GLP-1)改善阿尔茨海默病大鼠认知功能的机制。方法 以正常成年雄性SD大鼠为研究对象,将其随机分为正常对照组、AD模型组、AD模型+GLP-1干预组和AD模型+PPARγ抑制剂+GLP-1干预组; 其中AD模型组以侧脑室注射STZ(3 mg/kg,10 μL)制造AD模型,AD模型+GLP-1干预组在AD造模基础上每日腹腔注射利拉鲁肽(200 μg/kg,10 μL),连续给药28 d,AD模型+PPARγ抑制剂+GLP-1干预组在AD造模基础上侧脑室注射PPARγ抑制剂GW9662(2.5 nmol/g,10 μL),随后腹腔注射利拉鲁肽(200 μg/kg,10 μL)并连续给药28 d; 观察4组大鼠在Morris水迷宫中的学习和记忆能力变化; ELISA方法观察各组大鼠海马Aβ42的水平; Western blot观察各组大鼠海马PPARγ蛋白表达水平。结果 与AD模型组比较,GLP-1干预后的AD大鼠在Morris水迷宫中学习和记忆能力明显改善,海马Aβ42的水平显著降低,海马PPARγ蛋白表达水平显著升高(P<0.05); 与AD模型+GLP-1干预组比较,AD模型+PPARγ抑制剂+GLP-1干预组大鼠海马PPARγ蛋白表达水平显著降低,在Morris水迷宫中学习和记忆能力明显下降,海马Aβ42的水平显著增高(P<0.05)。结论 GLP-1可能通过激活PPARγ抑制Aβ 蓄积,从而起到改善阿尔茨海默病的认知功能作用。     

丹参多酚酸对慢性束缚应激后小鼠认知功能障碍的改善作用及相关机制

目的探讨丹参多酚酸对慢性束缚应激后小鼠认知功能障碍的改善作用及相关机制。方法采用3个月龄健康雄性昆明小鼠,随机分为对照组、应激组和丹参多酚酸干预组(SA组),每组14只小鼠。对照组和应激组小鼠每日腹腔注射生理盐水,SA组小鼠每日腹腔注射丹参多酚酸注射液;应激组和SA组小鼠每日腹腔注射后,束缚制动8 h,连续14 d。采用新异物体识别试验(NORT)、Morris水迷宫试验检测小鼠学习记忆能力的改变。采用HE染色观察海马神经元形态的改变。分别采用免疫组化法和实时荧光定量PCR检测海马脑源性神经营养因子(BDNF)蛋白及mRNA的表达。结果应激组小鼠NORT试验识别期对新物体的探索时间及新异物体差异指数均明显低于对照组和SA组(均P0.05)。应激组小鼠Morris水迷宫试验每日逃避潜伏期均明显长于对照组和SA组,第5 d探索平台次数明显少于对照组和SA组(均P0.05)。HE染色结果显示,对照组小鼠海马神经元形态完整,未见明显变化;应激组小鼠海马神经元细胞体积缩小,部分神经元细胞呈泡状改变;SA组可见到核轻度不规则,细胞形态接近于对照组神经元。应激组小鼠BDNF蛋白阳性细胞数和mRNA相对表达量均明显少于对照组和SA组(均P0.05)。结论丹参多酚酸干预能明显预防慢性束缚应激引起的认知功能损伤,其可能机制是能够抑制慢性应激所致海马BDNF表达的下降。     

促红细胞生成素对血管性痴呆模型大鼠认知功能、脑保护作用及海马α-微管蛋白表达的影响

目的 研究促红细胞生成素(Epo)对血管性痴呆(VD)模型大鼠认知功能、脑保护作用和海马α-微管蛋白(tubulin)表达的影响.方法 用"两血管阻断 硝普钠降压"法建立大鼠VD模型,并给予Epo腹腔注射治疗,采用Morris水迷宫试验检测大鼠的认知功能,Nissle染色、α-tubulin免疫组化染色观察细胞形态和Western blot法检测海马α-tubulin表达水平.并与VD大鼠及假手术组大鼠比较.结果 与VD组比较,Epo组大鼠水迷宫试验逃避潜伏期明显缩短(除试验第1 d)(均P＜0.05);海马神经元形态规则,尼氏小体数量多,α-tubulin阳性轴突数多,α-tubulin含量显著升高(P＜0.05).而Epo组与假手术组水迷宫试验逃避潜伏期及海马α-tubulin含量差异无统计学意义.结论 Epo可改善VD大鼠的认知功能,减轻缺血性脑损害,促进海马α-tubulin的表达.     

促红细胞生成素对创伤性脑损伤大鼠认知功能影响的实验研究

目的 评价促红细胞生成素(EPO)对脑外伤模型大鼠认知功能的作用,并探讨其影响机制.方法 48只雄性SD大鼠按随机数字表法分为对照组、假手术组、模型组和EPO治疗组.后2组建立液压冲击大鼠颅脑损伤模型,假手术组接受同样的操作但不接受液压冲击,对照组未经任何处理.伤后除EPO治疗组立即腹腔注射EPO(5000 U/kg)2 d外,另外3组同一时间腹腔注射等剂量生理盐水.于外伤后30 d应用Morris水迷官检测大鼠认知功能,伤后37 d应用免疫组化检测脑组织中脑源性生长因子(BDNF)的表达.结果定位航行实验结果显示训练后2、3、4、5 d各组大鼠寻找平台的潜伏期不同,对照组及假手术组潜伏期最短,模型组最长,EPO治疗组介于二者之间,差异有统计学意义(P<0.05);空间搜索实验结果显示各组大鼠在原来平台所在象限游泳时间的百分比不同,对照组及假手术组游泳时间的百分比最高,模型组最低,EPO治疗组介于二者之间,差异有统计学意义(P<0.05);免疫组化染色结果显示EPO治疗组大鼠脑组织BDNF的表达高于另外3组,差异有统计学意义(P<0.05).结论 液压冲击造成的颅脑损伤可损害大鼠的认知功能,外源性给予EPO可以改善外伤后大鼠的空间学习记忆能力,这可能与EPO促进BDNF的表达有关.     

外源性硫化氢对血管性痴呆模型大鼠学习记忆的影响

目的观察外源性硫化氢(Hydrogen Sulfide,H2S)对血管性痴呆大鼠(Vascular Dementia,Va D)学习记忆改善情况及血管性痴呆大鼠血浆硫化氢含量的变化。方法采用改良的四血管法(4-VO)复制大鼠Va D模型,将模型大鼠按给药干预时间分为1 d组、7 d组、30 d组,每组分为假手术组、模型组、低剂量组、高剂量组。低剂量组每日腹腔注射H2S供体Na HS 30μmol/kg,高剂量组每日腹腔注射H2S供体Na HS 100μmol/kg,假手术组与模型组每日腹腔注射等量生理盐水,然后进行Morris水迷宫检测大鼠学习记忆能力,用HE染色观察海马神经元的损伤情况,并测定Va D大鼠模型血浆硫化氢含量。结果与假手术组相比,模型组逃避潜伏期明显增长(P<0.05),血浆硫化氢浓度明显减少(P<0.05),海马神经元损伤严重;与模型组相比,低剂量组与高剂量组逃避潜伏期明显缩短(P<0.05),血浆硫化氢浓度明显增加(P<0.05),海马神经元损伤减轻,血管性痴呆大鼠学习记忆有所改善。结论硫氢化钠可改善Va D大鼠的认知水平和病理变化,其保护作用可能与提高硫化氢含量有关。     

17-β雌二醇对血管性痴呆大鼠认知功能和神经营养因子表达的影响

目的 研究17-β雌二醇对血管性痴呆(vascular dementia,VD)大鼠认知功能及脑组织神经生长因子(NGF)和脑源性神经营养因子(BDNF)表达的影响.方法 采用结扎双侧颈总动脉方法制备慢性前脑缺血动物模型,应用Y迷宫,免疫组化法和ELISA法检测腹腔注射17-β雌二醇60d后VD大鼠认知功能以及脑组织中NGF和BDNF含量变化.结果 与正常对照组对比,大鼠学习尝试次数,记忆测试10次的正确次数在造模60d后差异有显著性意义(P＜0.01),腹腔注射17-β雌二醇60d后,大鼠认知功显著改善;造模60d后的大鼠,其脑内NGF和BD-NF的含量较正常对照组显著增高,雌二醇组大鼠脑组织内NGF和BDNF的含量较模型组显著增高.结论腹腔注射17-β雌二醇可显著改善VD大鼠的认知功能,增加VD大鼠脑内NGF和BDNF含量.     

Epilepsy and anomalies of neuronal migration: MRI and clinical aspects

Neuronal migration disorders are the result of disturbed brain development. In such disorders, neurons are abnormally located. In diagnosing these conditions, magnetic resonance imaging is superior to any other imaging technique. This enables us to improve our knowledge of the clinical correlates of neuronal migration. With reference to migrational disorder, a retrospective study of all 303 patients with epileptic seizures referred for magnetic resonance imaging during a 3-year period was performed, 13 patients (aged 12-41, mean age 27) were identified. They represent 4.3% of the entire study group. Of the patients with known epilepsy, 6.7% and of the mentally retarded, 13.7% had migrational disorders. Four patients had schizencephaly as the dominant finding, one was classified as hemimegalencephaly, 2 had isolated heterotopias, and 6 had localized pachy- and/or poly-microgyria. The clinical pictures are complex. Ectopias of grey matter are recognised foci of epilepsy, but from an epileptological and a clinical viewpoint little attention has been given to these disorders. The present study shows that malmigration is not rare in epilepsy patients, especially not in the mentally retarded.     

Classification of methods in transcranial Electrical Stimulation (tES) and evolving strategy from historical approaches to contemporary innovations

Transcranial Electrical Stimulation (tES) encompasses all methods of non-invasive current application to the brain used in research and clinical practice. We present the first comprehensive and technical review, explaining the evolution of tES in both terminology and dosage over the past 100 years of research to present day. Current transcranial Pulsed Current Stimulation (tPCS) approaches such as Cranial Electrotherapy Stimulation (CES) descended from Electrosleep (ES) through Cranial Electro-stimulation Therapy (CET), Transcerebral Electrotherapy (TCET), and NeuroElectric Therapy (NET) while others like Transcutaneous Cranial Electrical Stimulation (TCES) descended from Electroanesthesia (EA) through Limoge, and Interferential Stimulation. Prior to a contemporary resurgence in interest, variations of transcranial Direct Current Stimulation were explored intermittently, including Polarizing current, Galvanic Vestibular Stimulation (GVS), and Transcranial Micropolarization. The development of these approaches alongside Electroconvulsive Therapy (ECT) and pharmacological developments are considered. Both the roots and unique features of contemporary approaches such as transcranial Alternating Current Stimulation (tACS) and transcranial Random Noise Stimulation (tRNS) are discussed. Trends and incremental developments in electrode montage and waveform spanning decades are presented leading to the present day. Commercial devices, seminal conferences, and regulatory decisions are noted. We conclude with six rules on how increasing medical and technological sophistication may now be leveraged for broader success and adoption of tES.     

Hepatic Considerations in the Use of Antiepileptic Drugs

Summary: Virtually all of the major antiepileptic drugs (AEDs) can cause hepatotoxicity, although fatal hepatic reactions are rare. The mechanisms, incidences, and risk profiles for such reactions differ from drug to drug. With carbamazepine and phenytoin, hepatotoxicity may be due to drug hypersensitivity. Although the profiles of patients at risk have not been well-defined for these two antiepileptic drugs, it would appear from reports in the literature that older adolescents and adults are at higher risk than children of developing serious or fatal hepatotoxicity. Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and 25% for carbamazepine. The risk profile for valproate fatal hepatotoxicity has been more clearly defined. Those at primary risk of fatal hepatic dysfunction are children under the age of 2 years who are receiving multiple anticonvulsants and also have significant medical problems in addition to severe epilepsy. The risk is considerably lower for patients over the age of 2 years on valproate monotherapy. In contrast to the risk profile with other AEDs, adults receiving valproate as monotherapy have the lowest risk of hepatotoxicity. Fatal hepatic dysfunction coincident with valproate may be the result of aberrant drug metabolism. Concomitant use of AEDs that induce microsomal P450 enzymes (e.g., phenytoin and phenobarbital) may enhance the production of a toxic metabolite, and hence the greater risk of hepatotoxicity with polypharmacy.     

Vascular Malformations and Epilepsy: Clinical Considerations and Basic Mechanisms

Summary: Vascular malformations (VMs) are associated with epilepsy. The natural history of the various VMs, clinical presentation, and tendency to provoke epilepsy determine treatment strategies. Investigations have probed the mechanisms of epileptogenesis associated with these lesions. Electrophysiologic changes are associated with epileptogenic cortex adjacent to VMs. Putative pathophysiologic mechanisms of epileptogenesis include neuronal cell loss, glial proliferation and abnormal glial physiology, altered neurotransmitter levels, free radical formation, and aberrant second messenger physiology.     

Neonatal Seizures: Problems in Diagnosis and Classification

Summary: The clinical identification of neonatal seizures is critical for the recognition of brain dysfunction; however, diagnosis is often difficult because of the poorly organized and varied nature of these behaviors. Current classification systems are limited in their ability to communicate motor, autonomic, and electroencephalo-graphic features of seizures precisely and to provide a basis for uniform effective diagnosis, therapy, and determination of prognosis. Recent investigations of neonates, utilizing bedside electroencephalographic/polygraphic/ video monitoring techniques, have provided the basis for improved diagnosis and classification of seizures in the newborn. These studies have demonstrated that not all clinical phenomena currently considered to be seizures require electrocortical epileptiform activity for their initiation or elaboration. In addition, the specific clinical character of the phenomena considered to be seizures, the clinical state of the infant, and the character of the EEG indicate the probable pathophysiological mechanisms involved and suggest probable etiologies, prognosis, and therapy. Similarities between animal models that demonstrate reflex physiology and neonates with motor automatisms and tonic posturing suggest that these clinical behaviors may not be epileptic in origin but, rather, primitive movements of progression and posture mediated by brainstem mechanisms. Although not all clinical behaviors currently considered to be neonatal seizures may have similar pathophysiological mechanisms, they are clinically significant because they all indicate brain dysfunction.     

Valproate Monotherapy in the Management of Generalized and Partial Seizures

Summary: For decades, therapeutic tradition has promoted the concept of polypharmacy in the management of epilepsy. In recent years, however, studies have shown that, for most patients, monotherapy can provide comparable or better seizure control than administration of multiple anticonvulsants, while diminishing the potential for adverse reactions, drug interactions, and poor compliance. Valproate is an important monotherapeutic agent that is highly effective in the control of idiopathic primary and secondarily generalized epilepsies, and partial seizures that do not generalize. Comparative studies have found that valproate is at least as effective as phenytoin and carbamazepine in the treatment of generalized and partial seizures. Given the similar efficacy, other factors such as pharmacokinetics and side effects may therefore determine anticonvulsant selection for monotherapy.     

Un nouveau cadre conceptuel de travail pour la psychiatrie

In an attempt to place psychiatric thinking and the training of future psychiatrists more centrally into the context of modern biology, the author outlines the beginnings of a new intellectual framework for psychiatry that derives from current biological thinking about the relationship of mind to brain. The purpose of this framework is twofold. First, it is designed to emphasize that the professional requirements for future psychiatrists will demand a greater knowledge of the structure and functioning of the brain than is currently available in most training programs. Second, it is designed to illustrate that the unique domain which psychiatry occupies within academic medicine, the analysis of the interaction between social and biological determinants of behavior, can best be studied by also having a full understanding of the biological components of behavior.     

Carbamazepine Efficacy and Utilization in Children

Summary: Carbamazepine is effective for preventing partial and generalized tonic-clonic seizures in children. Although absence epilepsies are more common in children than adults, an estimated 80% of children with epilepsy have seizure types or epilepsies that are potentially responsive to carbamazepine. The differential diagnosis of ictal staring is an especially important issue in children because absence and atypical absence seizures are more prevalent in children than adults. Age-related pharmacokinetic differences and drug interactions are major considerations in children. On average, children have higher clearance rates of carbamazepine, shorter half-lives, and higher ratios of carbamazepine-10, 11-epoxide to carbamazepine than adults. In addition, children with severe epilepsy are more likely to require multiple-drug therapy, which can lead to complex drug interactions. When carbamazepine is administered along with valproate, drug protein binding interactions can cause intermittent side effects.     

Special Pharmacokinetic Considerations in Children

Summary: Pediatric patients have greater degrees of pharmacokinetic variability and unpredictability than adults. This variability results from the effects of pharmacogenetics, age and growth, prior and current comedication, and disease. Newborns with seizures have the least predictable dosage requirements, and their needs change as drug-eliminating mechanisms mature in the neonatal period. Infants have the highest relative capacities to eliminate antiepileptics of any age group and require the largest relative doses. In addition to age-related trends, children demonstrate the same drug-specific, pharmacokinetic phenomena that adults do, including nonlinear phenytoin elimination, nonlinear valproate binding, and autoinduction of carbamazepine. Intercurrent illness and drug interactions further modify the age-related pharmacokinetic patterns in children and make dosage requirements even more unpredictable. Recent studies have shown that febrile illness can affect drug elimination, sometimes decreasing drug levels by 50% or more. Intermittent treatment with benzodiazepines administered either orally or rectally can be an important adjunct and help minimize this type of problem for children with marginally controlled epilepsy. Intermittent benzodiazepines are also helpful for children who have febrile seizures and who need only occasional antiepileptic protection.